Sodium hydride → 4-(2-chloro-1H-benzimidazol-6-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline

HRID 454180Notes

Reaction equation

HRID 454180 reaction equation
[Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1.[Cl-].[NH4+]>CN(C=O)C.ClCCl.CO.C(OCC)(=O)C>[Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1

Participants

8

Reactant 4

HCID 24758Sodium hydride2×HCID 25517Ammonium ChlorideHCID 117822304-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolineHCID 220309582-chloro-1H-benzo[d]imidazol-5-ol2×

Product 1

HCID 220306604-(2-chloro-1H-benzimidazol-6-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolineYield 16.3%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
100 °C

Procedure

To a portion of 2-chloro-5-hydroxybenzimidazole (191 mg, 0.75 mmol) in DMF (3 ml) was added sodium hydride (60 mg, 1.5 mmol) under argon at ambient temperature. Ten minutes later 4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 10), was added and the mixture heated at 100° C. for 2 hours. More 2-chloro-5-hydroxybenzimidazole (30 mg, 0.12 mmol) and sodium hydride (11 mg, 0.28 mmol) were then added as the reaction was found to be incomplete. The heating was continued for an additional 1 hour. Work-up using ethyl acetate and a saturated aqueous solution of ammonium chloride followed by drying of the organic phase (MgSO4) and evaporation of the solvent gave a crude product which was adsorbed on alumina using dichloromethane/methanol and purified by flash chromatography using neutral alumina and dichloromethane/methanol (98:2) as the eluent. Evaporation of the solvent and trituration in ether gave 4-(2-chloro-1H-benzimidazol-6-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (46 mg, 16%).

Workup

  1. additionwas added
  2. dry with materialby drying of the organic phase (MgSO4) and evaporation of the solvent
  3. customgave a crude product which
  4. custompurified by flash chromatography
  5. customEvaporation of the solvent and trituration in ether

Sources & evidence

ORD record
ord-9ed2198d475448fbb8e843800b1d5361
Source dataset
uspto-grants-2013_07
Patent number
US08492560B2

Reaction notes

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